Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report

Twenty-six published case reports and case reviews were identified that were considered relevant, a similar number to that identified in a recent review by Giusti et al. [50].

Concern about bisphosphonate use in relation to atypical subtrochanteric fractures arose from case reports that described patients with subtrochanteric fractures who had been exposed to bisphosphonates, particularly long-term treatment with alendronate (Fosamax®/Fosavance®, alendronate sodium, Merck Sharp & Dohme Limited). The association between long-term bisphosphonate use and unusual diaphyseal fractures was first described by Odvina et al. in 2005 [31] who reported nine patients with osteoporosis or osteopenia who had been treated with alendronate for 3–8 years and sustained atraumatic fractures in the course of their normal daily activities. Three patients had fractures of the femoral shaft and two had fractures of the proximal femur. Of these five patients, fracture healing was radiographically assessed in four. All four patients had delayed or absent fracture healing ranging from 4 months to 2 years while on alendronate treatment.

This and subsequent case reports are summarized in Table 1. The mean and median age of patients was 65 years (range 35–85). All cases involved treatment with alendronate, except for five patients who took risedronate (Actonel®, risedronate sodium, Procter and Gamble Pharmaceuticals) and three who took pamidronate (Aredia®, pamidronate disodium, Novartis Pharmaceuticals Limited). One patient had been taking ibandronate (Bonviva®/Boniva®, ibandronic acid, Roche) for 1 year following long-term alendronate use, and one had been taking risedronate for 5 years following 7 years of pamidronate use. There were no published case reports of subtrochanteric fractures following the use of once-yearly zoledronic acid 5 mg (Aclasta®/Reclast®, zoledronic acid anhydrous, Novartis Pharmaceuticals Limited), although cases following treatment with the monthly 4-mg dose have been reported [36, 38]. The mean and median duration of bisphosphonate use was 7.3 and 7.5 years, respectively (range 1–16), and the majority of patients had unilateral fractures (29 out of 43; 67.4%).

In addition to case reports, several case reviews have been published, which are summarized in Table 2. For example, the characteristics of low-trauma subtrochanteric and diaphyseal fractures were studied retrospectively by Neviaser et al. in all patients admitted to a US trauma centre over a 5-year interval (Table 2) [30]. Radiographs were examined by independent experts to identify fractures with a simple, transverse or short oblique pattern in areas of cortical hypertrophy with a cortical beak. The observers were blinded to patient characteristics, including alendronate use. Seventy patients were identified, of whom 25 were treated with alendronate. Nineteen out of 25 (76%) alendronate-treated patients had the radiographic pattern compared with one out of 45 (2%) non-alendronate-treated patients. Thus, the risk of having an ‘atypical’ subtrochanteric fracture pattern was significantly associated with alendronate use (odds ratio = 139; 95% confidence interval (CI) 19–939; p < 0.0001). The mean duration of treatment with alendronate was 6.2 years (6.9 years in those who had the fracture pattern vs 2.5 years in those who did not) [30]. The authors concluded that there are unique features to bisphosphonate-associated fractures.

Six studies that utilized control groups were identified that have investigated the association of subtrochanteric fractures with the use of bisphosphonates. In the study of Nieves et al. described above, the rate of subtrochanteric and femoral shaft fractures appeared to be higher than that of other fractures in women taking oral bisphosphonates (Fig. 2) [46], although there is no statistical information provided. It is not known whether excess fractures were due to trauma or not. The study concluded, however, that there was no evidence of an increase in the incidence of subtrochanteric or femoral shaft fracture between 1996 (around the time that bisphosphonates were first introduced) and 2006. Limitations of these data include the lack of radiological and clinical verification and no information on the type of bisphosphonate used or the duration of treatment.

In a study by Leung et al., ten patients with subtrochanteric fractures who had received alendronate were identified over a 5-year period. This included one patient who had taken alendronate for 1 year followed by ibandronate for 2 years [42]. The crude incidence of subtrochanteric/femoral diaphyseal fractures associated with prior bisphosphonate use increased over 5 years from 0% in 2003/2004 to 6% in 2004/2005, 8.6% in 2006/2007 and 25% in 2007/2008. This trend was despite a steady annual incidence of subtrochanteric/femoral diaphyseal fractures. It is difficult to draw meaningful conclusions from these data because of the very small sample size (ten subtrochanteric fractures in patients exposed to a bisphosphonate) and the lack of information on bisphosphonate use at other fracture sites. At best, the study documents the increasing use of bisphosphonates over the time of study.

In a small retrospective case–control study, Lenart et al. aimed to identify an association between low-energy subtrochanteric/femoral shaft fractures (according to the Müller AO classification) and long-term bisphosphonate use [29]. Forty-one low-energy subtrochanteric or femoral shaft fracture cases were identified and matched by age, body mass index and race to one low-energy intertrochanteric and femoral neck fracture each.

Fifteen out of the 41 (37%) cases of subtrochanteric or femoral shaft fracture cases were taking bisphosphonates, compared with nine out of 82 (11%) controls (OR = 4.4; 95% CI 1.8–11.4; p = 0.002). Alendronate was the bisphosphonate taken in all cases. Eight out of nine cases in the control group were taking alendronate (one had previously taken etidronate). A radiographic pattern of a simple transverse or oblique fracture, beaking of the cortex on one side and cortical thickening at the fracture site, was observed in ten of the 15 (67%) subtrochanteric/femoral shaft fracture cases taking bisphosphonate and three of the 26 (11%) subtrochanteric/femoral shaft fracture cases not taking bisphosphonate (OR = 15.3; 95% CI = 3.1–76.9; p < 0.001). The duration of bisphosphonate exposure was significantly longer in patients with this X-ray pattern [29].

Koh et al. carried out a retrospective clinical and radiological review of geriatric hip fracture patients at a Singapore tertiary centre over 4 years to assess features that predispose to complete stress fractures [38]. Thirty-two patients with spontaneous or low-energy fractures with metaphyseal–diaphyseal involvement and on bisphosphonate therapy were identified. All were on alendronate therapy except for one who was on monthly zoledronic acid 4 mg and one who had been on risedronate for 6 years following 4 years of alendronate. Of these, 16 patients (median duration of therapy 4.5 years) had radiographic evidence of lateral cortical thickening. Four had cortical stress lesions on the prefracture radiograph (group F) and 12 had cortical stress lesions on the contralateral femur (group C). The type of bisphosphonate taken by patients according to group was not detailed. All patients in group F experienced prodromal thigh discomfort, compared with 25% of patients in group C (p = 0.019), and radiographic evidence of a stress line across the cortical thickening occurred in 100% and 8% of patients, respectively (p = 0.003). At a median follow-up of 23 months, none of the patients in group C had developed a complete fracture. All of these patients except for one had discontinued bisphosphonate therapy; five had not taken any alternative therapy since discontinuation. Nevertheless, eight out of the 11 were asymptomatic, and no new cortical thickening was detected in any of the patients. The authors concluded that, in people taking long-term bisphosphonate therapy, symptomatic cortical stress reactions accompanied by evidence of a stress line across the cortical thickening suggest an increased risk of a complete stress fracture [38].

In the only population-based study that included radiological review of all cases, Schilcher and Aspenberg studied the incidence of stress fractures at the femoral shaft in bisphosphonate-treated patients in four hospitals in Sweden. Women aged over 55 years with fractures of the femoral diaphysis or subtrochanteric region were identified from the operation registry. Preoperative radiographs were examined to identify stress fractures, defined as a transverse fracture of the femoral shaft with cortical thickening. Of 91,956 women identified, 3,087 bisphosphonate users were identified, of whom five had femoral stress fractures. All of these five patients were aged >75 years, and their mean duration of treatment was 5.8 years [66]. Three patients that were not treated with bisphosphonates had stress fractures. All were aged <75 years. The annual incidence of femoral shaft stress fractures in bisphosphonate users was 1/1,000 per year (95% CI 0.3–2) vs 0.02/1,000 (0.004–0.1) per year in control patients. Thus, the risk of such fractures was estimated to be 46 times greater with bisphosphonate use (95% CI 11–200) [65]. An obvious weakness of the study is that, although the confidence intervals were corrected for sample size, the findings were based on just eight femoral shaft stress fractures. The results thus raise a hypothesis to be tested on larger samples.

A larger study is provided by Abrahamsen et al. who studied the epidemiology of subtrochanteric and diaphyseal femur fractures in patients in Denmark treated with alendronate [67]. However, in contrast to the Schilcher and Aspenberg report, in this study, radiographic fracture patterns were not reviewed, and thus, fractures were identified purely based on their location. In patients aged ≥60 years that had subtrochanteric, diaphyseal femur and hip fractures in 2005, the incidence of subtrochanteric (n = 898) and diaphyseal fractures (n = 720) were similar, and the ratio of high-to-low-energy trauma fractures was the same for each of these fracture types (approximately 2.5:1 for each). Exposure to alendronate was also similar between fracture types (approximately 7% each). Patients with subtrochanteric fractures and diaphyseal fractures were more likely to have taken glucocorticoids in the year before fracture than patients with hip fracture (10.9%, 8.4% and 6.5% of patients, respectively).

In a register-based matched cohort analysis, Abrahamsen et al. investigated whether the increase in risk of ‘atypical’ femur fracture in alendronate-treated patients was greater than the increase in risk of ‘typical’ osteoporotic femur fractures (‘typical’ and ‘atypical’ were not defined). In total, 15,187 patients who took alendronate for ≥6 months after the fracture event (the treatment cohort) were compared with two randomly assigned sex-, age- and fracture-matched controls (n = 10,374). The use of alendronate was associated with an increase in the hazard ratio (HR; adjusted for baseline comorbidities) for both subtrochanteric/diaphyseal fractures (HR = 1.46; 95% CI 0.91–2.35; p = 0.12) and hip fracture (HR = 1.45; 95% CI 1.21–1.74; p < 0.001). Subtrochanteric/diaphyseal fractures were equally common in the alendronate-treated (14% of hip fractures) and control patients (13%; p = 0.70). Both hip fractures and subtrochanteric/diaphyseal fractures were significantly lower in patients with higher adherence (HR = 0.47 [0.34–0.65; p < 0.001] and 0.28 [0.12–0.63; p < 0.01], respectively). In a sub-analysis of 178 compliant (medication possession ratio >80%) patients who took alendronate for >6 years, long-term alendronate use was associated with no change in both hip (HR = 1.24 [0.66–2.34]; p = 0.52) and subtrochanteric/diaphyseal fractures (HR = 1.37 [0.22–8.62]; p = 0.74). The incidence of subtrochanteric/diaphyseal fractures was similar in the long-term alendronate (10%) and control (12.5%) groups (10% vs 12.5%, respectively) [67].

This study, in a large number of patients, does not support the hypothesis that exposure to alendronate is associated with an increased frequency of subtrochanteric fractures compared with controls. However, the same study reported that treatment with alendronate was associated with an increased risk of hip fracture. This should not be interpreted as ‘alendronate causes hip fracture’, but only that high-risk patients are exposed to alendronate. The finding also illustrates the difficulties in the interpretation of retrospective observational studies, particularly accounting for selection bias that likely confounds the other much smaller observational studies.

Black et al. recently reported an analysis of subtrochanteric and diaphyseal fractures in the Fracture Intervention Trial (FIT) of alendronate and its extension [1, 2, 5, 68] and the HORIZON Pivotal Fracture Trial (PFT) of zoledronic acid 5 mg [3]. Twelve fractures in ten patients were documented in the subtrochanteric or diaphyseal region (Table 3) a combined rate of 2.3 per 10,000 patient-years [69]. However, radiographs were not available to confirm typical vs atypical radiographic features. There was no significant increase over placebo in the risk of subtrochanteric/diaphyseal fractures during the FIT, FIT Long-Term Extension (FLEX) or HORIZON-PFT trials. Compared with placebo, the relative hazard was 1.03 (95% CI 0.1–16.5) for alendronate use in the FIT trial, 1.5 (95% CI 0.3–9.0) for zoledronic acid in the HORIZON-PFT and 1.3 (95% CI 0.1–14.7) for continued alendronate use in the FLEX trial. The interpretation of this analysis is limited by the small number of events and the large confidence intervals.

Bilezikian et al. reported the incidence of subtrochanteric fractures in the randomized, placebo-controlled phase III studies of risedronate in post-menopausal osteoporosis, which enrolled more than 15,000 patients. In trials of up to 3 years duration, the mean incidence of subtrochanteric fractures was 0.14% in risedronate 2.5-mg treated patients (n = 4,998), 0.13% in risedronate 5-mg treated patients (n = 5,395) and 0.17% in placebo-treated patients (n = 5,363) [70]. In active control studies of risedronate involving various doses (35 mg once weekly, 75 mg on two consecutive days per month, 150 mg once monthly), no subtrochanteric fractures were reported, and the incidence of hip/femoral fractures was similar to that in the placebo-controlled studies [70].

The manufacturers of ibandronate have assessed their clinical trials database to determine the incidence of subtrochanteric and diaphyseal femoral fractures in women taking ibandronate for post-menopausal osteoporosis. Atypical fractures were defined as ‘mostly non-spine fractures including hip or femur fractures in the subtrochanteric region or shaft and occurring without trauma or in association with low-energy trauma’. For femur fractures, subtrochanteric fracture location was considered as atypical for osteoporosis-related fractures, defined as a region below the lesser trochanter and a junction between the proximal and middle third of the femoral shaft. In the pivotal trials (MF 4380, BONE, MOBILE and DIVA) [4, 71‐73], there were nine fracture cases corresponding to these defined locations and characteristics (subtrochanteric, femoral shaft, stress or multiple fractures): six occurred in placebo-treated patients (n = 1,924) and three in ibandronate-treated patients (n = 6,830). In addition, there was one identified case of a femoral shaft fracture in an ibandronate-treated patient in the extension and major phase IIIb trials (MOBILE LTE, DIVA LTE, MOTION and PREVENTION; n = 2,451) [74‐77]. Some fractures were reported without identifying the precise location. However, all of these fractures were associated with trauma and thus did not meet the definition for atypical fractures. An additional 5-year analysis of the marketed regimens of ibandronate (150 mg once monthly and 3 mg IV quarterly) was also carried out from the active comparator-controlled trials and their extensions (MOBILE, DIVA, MOTION, MOBILE LTE and DIVA LTE) [71, 72, 74, 75, 77]. No atypical subtrochanteric/diaphyseal femoral fractures were found for either of the marketed regimens (150 mg, n = 1,279; 3 mg, n = 469).

Since fractures are the clinical outcome of osteoporosis and no treatments are fully effective, fractures are expected in treated patients. It is likely, however, that the number of reports through pharmacovigilance will be small. The number of postmarketing reports of atypical stress fractures in association with alendronate to circa July 2008 was 115 (of which 84 were femur fractures) and included a large number of the cases reported in the literature [78].

Bilezikian et al. have reported that in more than 10 years of risedronate post-approval surveillance to September 2008 (18 million patient-years of exposure), the reporting rate for subtrochanteric fractures was <0.1 per 100,000 patient treatment years of exposure [70].

Postmarketing data from the manufacturers of zoledronic acid have revealed a similarly low rate of subtrochanteric fractures with zoledronic acid 5 mg. Using the last cutoff date for worldwide Health Authority Reporting prior to January 2010 (Periodic Safety Update Report v6) and assessing all adverse event reports for zoledronic acid 5 mg (579,501 patient-years of exposure), the rate of femoral subtrochanteric fracture reporting was three per 1,000,000 patient treatment years of exposure.

Postmarketing data from the manufacturers of ibandronate have also revealed a low rate of possible atypical fractures occurring in patients receiving ibandronate for the management of postmenopausal osteoporosis. According to their global safety database as of June 2009, cumulative postmarketing exposure of ibandronate yielded a crude reporting rate of possible atypical fractures of approximately one per 1,000,000 patients. Three of the cases involved alendronate treatment followed by ibandronate treatment and were reported in the case series of Ing-Lorenzini et al. [27].

In July 2008, the Pharmacovigilance Working Party (PhVWP) of the Committee for Medicinal Products for Human Use (CHMP) initiated a class review on bisphosphonates and atypical stress fractures. Marketing Authorization Holders supplied information about all preclinical, clinical and future studies, published case reports, postmarketing data, possible mechanisms and proposed risk-minimization activities. Following a PhVWP review of these data in December 2008, the CHMP concluded that there was an association between atypical stress fractures and long-term use of alendronate, due to the distinct fracture pattern, prodromal pain and poor fracture healing. However, the benefit–risk balance of alendronate use was considered favourable. The CHMP highlighted that there was uncertainty concerning a class effect for other bisphosphonates and that switching of bisphosphonates should be avoided at this time. Ultimately, the CHMP recommended that information about atypical stress fractures should be added to the product information for medicinal products containing alendronate [78]. Consequently, the labelling for alendronate (Fosamax®/Fosavance®, Merck Sharp & Dohme Limited) now includes a special warning/precaution for alendronate use, advising discontinuation of bisphosphonate therapy in patients with stress fracture pending evaluation, based on an individual benefit–risk assessment [22, 79]. Alendronate is the only bisphosphonate for osteoporosis treatment that currently carries this warning.

In addition to the 2008 class review, the EMEA released a statement in August 2009 highlighting their 2010 priorities for drug safety research with regards to the long-term adverse skeletal effects of bisphosphonates: (1) generate methodologies to study the link between bisphosphonate use and long-term adverse skeletal events in human populations and (2) measure the incidence of stress/insufficiency fractures in association with high-dose/long-term use of bisphosphonates by class, compound, mode of administration, dose etc. Methods could include meta-analysis or nested case–control studies [80].

In June 2008, the US Food and Drug Administration (FDA) initiated a review of bisphosphonates for a possible association with increased risk of atypical subtrochanteric femur fractures. All available case reports and clinical trial data were requested from all bisphosphonate drug manufacturers and were reviewed alongside the registry data from the large observational study of Abrahamsen et al. [67]. In March 2010, the FDA announced that the data reviewed had not shown a clear connection between bisphosphonate use and the risk of atypical subtrochanteric fractures. Physicians were urged to continue to follow the labelling when prescribing bisphosphonates and patients were instructed not to discontinue their medication unless instructed to do so by their physician [81].

The pathophysiology of atypical low-trauma subtrochanteric fractures following bisphosphonate use is not known. However, preclinical and clinical studies of the effects of bisphosphonates on bone suggest that there are several possible mechanisms that work either alone or in tandem. The organic matrix of the bone determines its toughness, and this matrix is partly made up of bone collagen, which impacts on the bone’s mechanical properties. Bisphosphonate use may negatively affect collagen by preventing or reducing its maturation [82], although this finding has not been consistently replicated [83]. Bisphosphonates may also affect bone mineralization density distribution (BMDD). The more heterogeneous the BMDD, the slower that cracks in the bone will develop and the lower the risk of new cracks and fractures forming [84]. As bisphosphonate treatment reduces bone turnover, the increase in overall mineralization leads to more homogeneous bone—as evidenced by a narrow BMDD [85, 86]—and thus an increased risk of cracks and fractures. Reduced bone turnover also increases the accumulation of microdamage, as cracks are not repaired [87], and reduces bone toughness, which contributes to the increased susceptibility of bone to new cracks [88‐90]. Finally, bisphosphonates have differing impacts on different types of fracture. Acute fractures of long bone are not affected by bisphosphonates in the initial healing stages [91‐93], as they heal via endochondral ossification. However, stress fractures heal by normal bone remodelling, and thus, bisphosphonates may prevent or delay healing, increasing the likelihood of a complete fracture with little or no trauma. Several reports have reported on bone quality in people with low-trauma fractures taking bisphosphonate therapy.

For example, Odvina et al. reported that cancellous bone histomorphometry in alendronate-treated patients (3–8 years) who sustained spontaneous non-vertebral fractures showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was also low in most patients, and eroded surface decreased in half [31]. Odvina et al. reported similar findings in a later report in a comparable patient population [58]. In a case report by Armamento-Villareal et al. of a man who had a low-trauma subtrochanteric fracture after discontinuing 6 years of alendronate treatment, a bone biopsy showed severely decreased trabecular connectivity, a lack of osteoid on trabecular surfaces and an absence of tetracycline labelling [53]. Armamento-Villareal et al. later reported that of 15 bisphosphonate-treated patients (2–10 years; Table 2) who underwent bone biopsies following a low-energy cortical (femoral shaft, pelvis, rib, metatarsal, ankle) fracture, ten had an absence of double-tetracycline label, reduced osteoid surface and thickness suggestive of suppressed trabecular bone remodelling. However, there was no difference in cortical thickness between patients with suppressed (n = 10) and normal (n = 5) turnover [25]. Recent findings by Somford et al., however, suggest an alternative pathophysiology for subtrochanteric fractures associated with bisphosphonate treatment. In a patient who was treated with alendronate for 8 years and subsequently developed spontaneous bilateral subtrochanteric/diaphyseal fractures, biopsies showed a marked decrease in bone formation as expected; however, this was not coupled with the expected decrease in bone resorption. In fact, bone resorption parameters such as osteoclast number were markedly increased in the femur sample. In addition, there was no evidence of hypermineralized bone. This suggests that an imbalance between bone resorption and bone formation at the affected femur—the cause of which is currently unknown—rather than excessive suppression of bone turnover may be the underlying mechanism for subtrochanteric/diaphyseal femoral fractures in bisphosphonate-treated patients [94].